CD80, also known as B7-1, is one of the B7 family of membrane-bound proteins involved in immune regulation by delivering costimulatory or coinhibitory responses through their ligand binding activities. Other members of the B7 family of proteins include CD86 (B7-2), inducible costimulator ligand (ICOS-L), programmed death-1 ligand (PD-L1; B7-H1), programmed death-2 ligand (PD-L2; B7-H2), B7-H3, and B7-H4. CD80 is a transmembrane protein expressed on the surface of T cells, B cells, dendritic cells and monocytes, and binds to the receptors CD28, CTLA4 (CD152), and PD-L1. CD80 and CD86 and their receptors CTLA4 and CD28 operate as a costimulatory-coinhibitory system, for example, to control T cell activation, expansion, differentiation, and survival. CD80 and CD86 interaction with CD28 results in costimulatory signals that lead, for example, to activation of T cell responses. CD80, in turn, stimulates upregulation of CTLA4, which, upon binding to CD80, acts to suppress the T cell response previously triggered by CD80/CD28 interactions. This feedback loop allows for fine control of immune responses.
CD80 has also been shown to interact with another B7 family member, PD-L1 with similar affinity to CD28, whereas CD86 does not interact with PD-L1. PD-L1 is one of two ligands for the programmed death-1 (PD-1) protein, which is also involved in T cell regulation. Specifically, expression of PD-1 on T cells may be induced after T cells have been activated, and binding of PD-1 to PD-L1 downregulates T cell activity by promoting T cell inactivation. Many tumor cells express PD-L1 on their surface, potentially leading to PD-1/PD-L1 interactions and the inhibition of T cell responses against the tumor. This observation has led to the development of inhibitors of the PD-1/PD-L1 interaction as cancer therapeutics designed to stimulate natural immune responses against tumors in patients.
Binding of CD80 to PD-L1 may serve as an alternative mechanism to block the PD-1/PD-L1 interaction and prevent inhibition of T cell responses at the site of a tumor. At the same time, however, increased levels of CD80 might also be available to bind to CD28 and to induce CTLA4, thus either inducing or inhibiting T cell responses. Some soluble forms of CD80 may also function to block CTLA4 activation by blocking endogenous CD80 activity. In addition, different soluble CD80 protein forms may have different effects on tumor growth through other interactions between the protein forms and tumor cells whose impact cannot be predicted in advance of testing. How various soluble forms of CD80 actually impact tumor growth in vivo has also not previously been directly tested. The present inventors have developed a set of CD80 extracellular domain (ECD) fusion molecules with particularly potent effects on tumor growth in a mouse model, both when administered alone, and when administered in conjunction with a PD-1/PD-L1 inhibitor. Based on the data shown in the working examples below, embodiments herein may provide superb therapeutic effects in cancer treatment.